Methods for treating disseminated intravascular coagulation by inhibiting MASP-2 dependent complement activation

Abstract

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. In one embodiment, the invention provides methods of treating a subject suffering from a complement mediated coagulation disorder, such as disseminated intravascular coagulation. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation. In some embodiments, the MASP-2 inhibitory agent inhibits cellular injury associated with MASP-2-mediated alternative complement pathway activation, while leaving the classical (C1q-dependent) pathway component of the immune system intact. In another aspect, the invention provides compositions for inhibiting the effects of lectin-dependent complement activation, comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
       1. A method of inhibiting systemic coagulation in a subject suffering from, or deemed to be at risk for developing, disseminated intravascular coagulation, comprising:
 (a) determining whether the subject exhibits clinical evidence indicating that the subject is suffering from or is deemed to be at risk for developing disseminated intravascular coagulation; and 
 (b) administering to the subject suffering from or deemed to be at risk for developing disseminated intravascular coagulation an amount of a MASP-2 inhibitory agent effective to inhibit systemic coagulation, wherein the MASP-2 inhibitory agent comprises an antibody or fragment thereof that specifically binds to a portion of SEQ ID NO:6. 
 
     
     
       2. The method of  claim 1 , wherein the disseminated intravascular coagulation is secondary to a disease or condition selected from the group consisting of trauma, sepsis, infection, malignancy, transplant rejection, transfusion reaction, obstetric complication, vascular aneurysm, hepatic failure, heart stroke, burn, radiation exposure, surgery and severe toxic reaction. 
     
     
       3. The method of  claim 1 , wherein the MASP-2 inhibitory agent specifically binds to a polypeptide comprising SEQ NO: 6 with an affinity of at least 10 times greater than it binds to a different antigen in the complement system. 
     
     
       4. The method of  claim 1 , wherein the MASP-2 inhibitory agent binds to the polypeptide at a location within amino acid residues 1-176 of SEQ ID NO:6. 
     
     
       5. The method of  claim 1 , wherein the antibody or fragment thereof is monoclonal. 
     
     
       6. The method of  claim 1 , wherein the antibody or fragment thereof is polyclonal. 
     
     
       7. The method of  claim 1 , wherein the antibody or fragment thereof is a recombinant antibody. 
     
     
       8. The method of  claim 1 , wherein the antibody has reduced effector function. 
     
     
       9. The method of  claim 1 , wherein the antibody is a chimeric, humanized or human antibody. 
     
     
       10. The method of  claim 1 , wherein the antibody is produced in a MASP-2 deficient transgenic animal. 
     
     
       11. The method of  claim 1 , wherein the MASP-2 inhibitory agent selectively inhibits MASP-2-dependent complement activation without substantially inhibiting C1q-dependent complement activation. 
     
     
       12. The method of  claim 2 , wherein the disseminated intravascular coagulation is secondary to trauma. 
     
     
       13. The method of  claim 2 , wherein the disseminated intravascular coagulation is secondary to a bacterial infection. 
     
     
       14. The method of  claim 13 , wherein the bacterial infection is a  N. meningitidis  infection. 
     
     
       15. The method of  claim 1 , wherein he MASP-2 inhibitory agent is administered systematically to the subject. 
     
     
       16. The method of  claim 1 , wherein the MASP-2 inhibitory agent is administered subcutaneously to the subject. 
     
     
       17. The method of  claim 12 , wherein the trauma is neurological trauma. 
     
     
       18. The method of  claim 1 , wherein the clinical evidence includes one or more of the following (i) complement C3 activation beyond 30% of the vascular pool, (ii) a decrease or conversion in C5 level, (iii) vasodilatation, and/or (iv) fluid loss to tissues.